Oral therapeutic system having systemic action

ABSTRACT

The invention relates to a therapeutic system for peroral administration and having systemic action, which system is in the form of a coated and/or laminated mono-compartment system for administering carbamazepine. The therapeutic system comprises 
     (a) a wall made of a material which is permeable to water and impermeable to the components of the drug-containing core, 
     (b) a core containing finely particulate carbamazepine as drug and, as auxiliaries, a protective colloid that inhibits the crystal growth of carbamazepine in the presence of water, a swellable hydrophilic polymer and, optionally, a water-soluble compound for inducing osmosis and/or further pharmaceutically acceptable excipients, and 
     (c) a passageway through the wall (a) for delivering the core components to the environmental body fluid. The therapeutic system can be used as an anticonvulsive for the treatment of convulsive states, especially epileptic states.

.Iadd.This application is a continuation of application Ser. No.07/619,160, filed Nov. 28, 1990, now abandoned which was a reissue ofSer. No. 07/079,055, filed Jul. 29, 1987, now U.S. Pat. No. 4,857,336,issued Aug. 15, 1989. .Iaddend.

The present invention relates to an oral therapeutic system forcarbamazepine with a compartment for the drug formulation, and to aprocess for the preparation thereof as well as to the therapeutic use ofsaid system as anticonvulsant.

Carbamazepine, 5H-dibenz[b,f]azepine-5-carboxamide (Tegretol®,Tegretal®, Ciba-Geigy) is used as anticonvulsant and analgesic.Commercial dosage forms are 200 mg tablets and 2% syrups.

Oral therapeutic systems for effecting a systemic action and theiradvantages over conventional dosage forms such as tablets and syrups areknown. By means of such systems it is possible to achieve a prolongedrelease of active substance at a constant therapeutic level. In theOROS® system (oral osmotic system; Alza Corp.), which has been describedby F. Theeuwes in J. Pharm. Sc., Vol. 64, 12 1987-1991 (1975), and whichis in the form of a conventional tablet, aqueous body fluids enter thesystem continuously through the outer layer acting as semi-permeablemembrane and dissolve the solid active substance core. Given sufficientwater-solubility, the pressure that is built up causes the solutioncontaining the drug to be released through an orifice having a diameterof c. 100-150 μm.

When the active substance present in the core is able to produce asufficiently high osmotic pressure of its own, this dosage form effectsthe release of a sufficient amount of the drug and thus achieves thedesired therapeutic effect. The prerequisite for achieving this effectis a sufficiently high concentration of water-soluble drug and acorrespondingly low concentration of excipients in the core.

For this reason OROS® systems are unsuitable for sparingly solubledrugs. In particular, the osmotic pressure of a drug such ascarbamazepine, which is administrable in high dosage, is too low. Tosolve this problem U.S. Pat. No. 4 111 202 postulates the use oftwo-compartment systems for sparingly soluble drugs ("push-pull"systems), which systems contain the drug or drug formulation in onecompartment and water-soluble auxiliaries, e.g. salts or sugars forproducing an osmotic pressure, in a second compartment underneath. Thetwo compartments are separated from each other by a flexible partitionand sealed externally by a rigid but water-permeable semi-permeablemembrane. When water enters the compartment, the osmotic pressurethereby produced causes an increase in volume of the lower compartment.As the semi-permeable wall is rigid, the osmotic pressure acts solely onthe expanding flexible partition and expels the contents of the drugcompartment from the system.

The preparation of push-pull systems is technically complicated, as aflexible partition consisting of a material different from that of thesemi-permeable membrane has to be incorporated into such a dosage form.In addition, for sparingly soluble high-dosage drugs like carbamazipine,which is administered in a dosage of e.g. more than 200 mg, it is onlypossible to prepare voluminous push-pull systems whose ingestion,especially after an epileptic attack, is problematical.

Push-pull systems for sparingly soluble drugs without a partition aredisclosed in European patent application No. 52917. The osmotic drivingmember is present in the drug compartment. The compartment underneathconsists of a swellable polymer such as polyvinylpyrrolidone. Theosmotic pressure built up effects a increased absorption of fluid intothe system, whereby the swelling is accelerated. The pressure exerted byswelling effects an expansion in volume only of that compartment whichconsists of swellable polymer and, as the semi-permeable membrane isrigid, expels the contents of the drug compartment through an orifice.

The dosage form disclosed in European patent application No. 52917 is tobe understood as a two-layered tablet with coating. Compared withconventional coated tablets, the preparation of these tablets iscomplicated. Thus the compression must be carried out in two steps. Inthe usual compression of different granulates, stringent demands aremade of the uniform particle size of the granulate components that arecompressed together. Reference is made in this connection to thedescription of multi-layered tablets and the technical problems andrequirements made of the granulates employed in "Hagers Handbuch derPharmazeutischen Praxis", Springer Verlag 1971 (hereinafter referred tofor short as "Hager"), Vol. VIIa, p. 710 bottom and p. 733 bottom to p.725.

A further problem is that, when using anhydrous carbamazepine (amorphousor crystalline), dihydrates form on contact with water (q.v. J. Pharm.Soc. Jpn. No. 2, 184-190, 1984). The dihydrates are in the form ofneedles which may grow to a particle size of c. 500 μm in length. Theknown push-pull systems cannot function satisfactorily with suchdihydrate crystals, as the expanded bulky crystals block the orifice ofthe therapeutic system. Therefore only milled carbamazepine crystalswhose maximum size is governed by the diameter of the orifice of thesystem are suitable. Up to now it has only been possible to obtain millcarbamazepine dihydrate crystals of suitable size by means of the wetmilling process. Because the grinding stock has to be dried, dry millingprocesses are problematical, for the anhydrous carbamazepine forms againat c. 37° C. The wet milling process itself also has disadvantages, asthe suspension agent has to be removed in a separate step.

It is the object of the present invention to provide an oral therapeuticsystem for carbamazepine having only one drug compartment, the size ofwhich corresponds to that of the known prior art oral osmoticmonocompartment systems, and to prevent the crystal growth ofcarbamazepine by addition of a suitable auxiliary, so that the twocumbersome steps of preparing the hydrate form and wet milling areavoided.

This object is achieved by choice of a suitable protective colloid whichinhibits the crystal growth of carbamazepine hydrate forms in oralosmotic systems, keeps the particle size of the hydrate crystalssubstantially constant, and effects a sufficient rate of release fromthe monocompartment system.

The invention relates to a therapeutic system having systemic action forperoral administration in the form of a coated and/or laminatedmonocompartment system for the administration of carbamazepine. Thetherapeutic system of the invention comprising

(a) a wall made of a material which is permeable to water andimpermeable to the compartments of the drug-containing core,

(b) a core containing finely particulate carbamazepine as drug and, asauxiliaries, a protective colloid that inhibits the crystal growth ofcarbamazepine in the presence of water, a swellable hydrophilic polymerand, optionally, a water-soluble compound for inducing osmosis and/orfurther pharmaceutically acceptable excipients, and

(c) a passageway through the wall (a) for delivering the core componentsto the environmental body fluid.

The invention further relates to a process for the preparation of saidoral therapeutic system and to a method of inhibiting the crystal growthof carbamazepine hydrate forms in an oral therapeutic system, as well asto the use of said system as anticonvulsant and/or analgesic.

The definitions and terms employed throughout this specification havethe following preferred meanings within the scope of the description ofthis invention.

The wall (a) made of material which is permeable to water andimpermeable to the components of the active substance core may beunderstood as being a semi-permeable membrane which is permeable to thepassage of water but substantially impermeable to the passage ofcomponents present in the core of the dosage form, e.g. drug, swellablepolymer, osmotic agent and the like.

Suitable materials for forming the semi-permeable wall are e.g. thepolymeric microporous materials described in the literature, e.g. inU.S. Pat. Nos. 3,916,899 and 3,977,404, and which are not metabolised inthe gastrointestinal tract, i.e. which are excreted intact. For example,it is possible to use acylated cellulose derivatives (cellulose esters)which are substituted by one to three acetyl groups or by one or twoacetyl groups and a further acyl radical other than acetyl, e.g.cellulose acetate, cellulose triacetate, agar acetate, amylose acetate,cellulose acetate ethyl carbamate, cellulose acetate phthalate,cellulose acetate methyl carbamate, cellulose acetate succinate,cellulose acetate dimethylaminoacetate, cellulose acetate ethylcarbonate, cellulose acetate chloroacetate, cellulose acetate ethyloxalate, cellulose acetate methyl sulfonate, cellulose acetate butylsulforate, cellulose acetate propionate, cellulose acetatediethylaminoacetate, cellulose acetate octate, cellulose acetatelaurate, cellulose acetate p-toluenesulfonate, cellulose acetatebutyrate and other cellulose acetate derivatives. Suitablesemi-permeable membrane materials are also hydroxypropyl methylcelluloseand polymeric epoxides, copolymers of alkylene oxides and alkyl glycidylethers, polyglycols or polylactic acid derivatives and furtherderivatives thereof. It is also possible to use mixtures, e.g. ofwater-insoluble acrylates (e.g. the copolymer of ethyl acrylate andmethyl methacrylate).

Carbamazepine is used in freely particulate form for the therapeuticsystem of the present invention. The expression "freely particulateform" will be understood as comprising micronised amorphous anhydrousand micronised crystalline hydrate forms. Micronised crystallineanhydrous forms are preferred. The particle size must be chosen suchthat unhindered release of the active substance through the orifice ofthe wall (a) is ensured, which orifice has a preferred diameter of c.0.4-min. Further, this particle size permits enhanced resorption ofdispersed particles of the sparingly soluble drug. In a preferredembodiment of the dosage form of this invention, anhydrous crystals ofcarbamazepine having an average particle size smaller than 100 μm,preferably smaller than 20 μm, are used.

Protective colloids which inhibit the crystal growth of carbamazepine inthe presence of water delay the formation of crystal forms that provetroublesome on a production scale and are unsuitable for the preparationof oral therapeutic systems, e.g. large hydrate crystals of fine grainparticles. Surprisingly, such protective colloids inhibit in particularthe formation of large needle-shaped crystals (dihydrate crystals) ofanhydrous modifications or amorphous particles. As mentioned previously,the formation of large needle-shaped crystals is deleterious to thecontinuous release performance of the therapeutic system, as thepassageway for the delivery of the active substance becomes blocked andconsequently release of the drug is hindered.

Particularly suitable protective colloids are dispersible celluloseethers, e.g. alkylated cellulose such as methyl or ethyl cellulose,hydroxypropyl cellulose, hydroxypropyl alkylcellulose, e.g.hydroxypropyl methyl- or ethylcellulose, carboxymethyl cellulose in saltform, e.g. sodium carboxymethyl cellulose, or carboxymethylalkylcellulose in salt form, e.g. sodium carboxymethyl methylcelluloseor sodium carboxymethyl ethylcellulose.

The most suitable protective colloids are methylated cellulose esters,e.g. methyl cellulose having a methoxy content of c. 27.0 to 32.0% and adegree of substitution of c. 1.75 to 2.1, or hydroxypropylmethylcellulose having a methoxy content of c. 16.0 to 30% and ahydroxypropoxy content of 4.0 to 32.0%. The oral therapeutic system ofthis invention contains protective colloids such as hydroxypropylmethylcellulose in a preferred mount by weight of c. 5-20%, based on theamount of active substance.

The addition of such protective colloids inhibits or slows down thegrowth observable in aqueous phase of anhydrous carbamazepinemicrocrystals having a size of up to c. 100 μm, preferably up to c. 20μm, or hydrates thereof of similar size, to needle-shaped hydrateshaving a size of up to c. 500 μm.

The therapeutic system of this invention is therefore able to releasecarbamazepine microcrystals having a size of up to c. 20 μm into thegastrointestinal tract, so that this drug, in particularly finelydispersed form, can be dissolved and resorbed.

The swellable hydrophilic polymer present in the core (b) is anexcipient that interacts with water or the aqueous fluid present in thegastrointestinal tract, swells, and expands to a state of equilibrium.The swellable hydrophilic polymer has the ability to absorb largeamounts of water and to induce the pressure necessary for thetherapeutic system to function. As the semi-permeable wall (a) is rigid,or at least of only limited elasticity, the pressure induced byexpansion is compensated for by release of the material present in thecore through the passageway (c) provided in the semi-permeable wall.

Examples of suitable swellable hydrophilic polymers are polymers whichmay be uncrosslinked or in which, if crosslinked, the crosslinks areformed by covalent or ionic bonds. The polymer retains the ability toswell in the presence of fluids without dissolving completely in thefuid when crosslinked. The polymers can be of plant, animal, mineral orsynthetic origin.

Polymers which are paraticularly suitable for use in the practice ofthis invention are water-soluble aliphatic or cyclic poly-N-vinylamides,e.g. poly-N-vinylmethylacetamide, poly-N-vinylethylacetamide,poly-N-vinylmethylpropionamide, poly-N-vinylethylpropionamide,poly-N-vinylmethylisobutyramide, poly-N-vinyl-2-pyrrolidone,poly-N-vinyl-2-piperidone, poly-N-vinyl-ε-caprolactam,poly-N-vinyl-5-methyl-2-pyrrolidone orpoly-N-vinyl-3-methyl-2-pyrrolidone, preferably poly-N-vinylpyrrolidonehaving an average molecular weight of c. 10,000 to 360,000, swellablepolyvinyl acetate or polyvinyl alcohol having a different acetate orresidual acetate content, e.g. polyvinyl acetate having a molecularweight of c. 5000 to 400,000, or polyvinyl alcohol having a degree ofhydrolysis of c. 85-98% and a degree of polymerisation of c. 500 to2500, alkylene oxide homopolymers, e.g. polypropylene oxide, preferablyethylene oxide homopolymers having a degree of polymerisation of c. 2000to 100,000 and known e.g. under the registered trademark Polyox® (UnionCarbide), as well as the known protective colloids of the swellablecellulose ether type, e.g. methyl cellulose, ethyl cellulose orhydroxypropyl cellulose or hydroxypropyl methylcellulose, preferablyhaving a molecular weight higher than 10,000, or mixtures of saidswellable hydrophilic polymers.

Further suitable swellable hydrophilic polymers are homopolymers such aspolyhydroxy alkylmethacrylate having a molecular weight of 5000 to5000,000, anionic or cationic hydrogels, mixtures of agar andcarboxymethyl cellulose, swellable agents consisting of methyl cellulosein admixture with lightly crosslinked agar, water-swellable polymerswhich can be obtained by dispersing the freely particulate copolymer ofmaleic anhydride and styrene, as well as polyalkylenes, e.g.polyethylene, polypropylene or polyisobutylene.

In a preferred embodiment of the invention, the swellable hydrophilicpolymer is a copolymer of vinylpyrrolidone and vinyl acetate, preferablyhaving a molecular weight of 60,000±15,000. The ratio ofvinylpyrrolidone and vinyl acetate in the copolymer is c. 60:40 (% byweight). The copolymer of vinylpyrrolidone and vinyl acetate has thefollowing properties:

Purity: 95% (remainder: water), insoluble in ether and aliphatichydrocarbons, very readily soluble in water, ethyl and isopropylalcohol, methylene, chloride, glycerol and 1,2-propylene glycol, pH of a10% aqueous solution 3-5, viscosity (in 10% aqueous solution): 5 mPa·s(q.v. H. P. Fiedler, Lexikon der Hilfsstoffe, Editio Cantor 1982).

Copolymers of vinylpyrrolidone and vinyl acetate are known and can beobtained in a manner known per se in any ratio of the monomers. Thepreferred 60:40 copolymer is e.g. available under the registeredtrademark Kollidon® VA 64 (BASF).

In a particularly preferred embodiment of the invention, a mixture ofthe copolymer of vinylpyrrolidone and vinyl acetate with an ethyleneoxide homopolymer is used as swellable hydrophilic polymer. This mixturehas the surprising advantage that the pressure induced by the swellingof the polymer does not lead to rupture of the system and the rate ofswelling is uniform, so that approximately constant mounts of activesubstance are released by the system.

The ethylene oxide homopolymer used in the mixture is Polyox® having amolecular weight higher than 1.0×10⁶.

In this preferred embodiment of the invention a 1:1 mixture (% byweight) of the copolymer of vinyipyrrolidone and vinyl acetate(commercial form: Kollidon® VA 64) with the ethylene oxide homopolymer(commercial form: Polyox®, mol. wt. 5×10⁶) is most conveniently used.

The core of the therapeutic system can contain c. 5-60% by weight ofswellable hydrophilic polymer, based on the total weight of thetherapeutic system.

The optional water-soluble compounds for inducing osmosis which may alsobe present in the core in addition to the swellable hydrophilic polymerinduce an osmotic pressure after water penetrates the semi-permeablemembrane and increase the pressure exerted by the hydrophilic polymer.

Water-soluble compounds suitable for inducing osmosis are, in principle,all pharmacologically acceptable water-soluble compounds. e.g. thewater-soluble excipients referred to in pharmacopeias or in "Hager" aswell as in Remington's Pharmaceutical Sciences. Especially suitable arepharmaceutically acceptable water-soluble salts of inorganic or organicacids or nonionic organic compounds of particularly high watersolubility, e.g. carbohydrates such as sugar, or amino acids.

Examples of such water-soluble compounds for inducing osmosis are:inorganic salts such as magnesium chloride or magnesium sulfate,lithium, sodium or potassium chloride, lithium, sodium or potassiumhydrogen or dihydrogen phosphate, salts of organic acids such as sodiumor potassium acetate, magnesium succinate, sodium benzoate, sodiumtitrate or sodium ascorbate; carbohydrates such as sorbitol or mannitol(hexite), arabinose, ribose or xylose (pentosene), glucose, fructose,galactose or mannose (hexosene), sucrose, matrose or lactose(disaccharides) or raffinose (trisaccharides); water-soluble amino acidssuch as glycine, leucine, alanine or methionine, urea and the like, andmixtures thereof. These water-soluble excipients may be present in thecore in amounts by weight of c. 0.01 to 35%, based on the total weightof the therapeutic system.

In addition to containing the water-soluble compounds for inducingosmosis and the swellable hydrophilic polymer, the core (b) can containfurther pharmaceutically acceptable excipients.

Preferred additional excipients are surface-active compounds. i.e.surfactants, e.g. anionic surfactants of the alkylsulfate type such assodium, potassium or magnesium n-dodecylsulfate, n-tetradecylsulfate,n-hexadecylsulfate or n-octadecylsulfate, of the alkyl ether sulfatetype, e.g. sodium, potassium or magnesium n-dodecyloxyethyl sulfate,n-tetradecyloxyethyl sulfate, n-hexadecyloxyethyl sulfate orn-octadecyloxyethyl sulfate; or of the alkylsulfonate, type e.g. sodium,potassium or magnesium n-dodecanesulfonate, e.g. sodium, potassium ormagnesium n-tetradecanesulfonate, n-hexadecanesulfonate orn-octadecanesulfonate.

Further suitable surfactants are nonionic surfactants of the fatty acidpolyhydroxy alcohol ester type such as sorbitan monolaurate, sorbitanmonooleate, sorbitan monostearate or sorbitan monopalmitate, sorbitantristearate or triolate, polyethylene glycol fatty acid ester such aspolyoxyethyl stearate, polyethylene glycol 400 stearate, polyethyleneglycol 2000 stearate, preferably ethylene oxide/propylene oxide blockpolymers of the Pluronics® (BWC) or Synperonic® (ICI) type.

Further excipients are those customarily used in tabletting for thepreparation of granulates, e.g. binders, lubricants, glidants,dispersants, fillers and the like. Thus is it possible to useconventional auxiliaries such as lactose, sacchrose, sorbitol, mannitol,starch, e.g. potato starch, corn starch or amylopectin, or cellulose,especially microcrystalline cellulose, or magnesium stearate, inaddition to the cited excipients.

The expression "passageway through the walls (c) for delivering thecomponents present in the core to the environmental aqueous body fluid"encompasses means and methods suitable for releasing the drugformulation from the core of the therapeutic system. The expressioncomprises passages, orifices, bores, apertures and the like through thewall (a) acting as semi-permeable membrane which establish a connectionbetween the surface of the wall and the core. In one embodiment of theinvention, two or more passageways can be provided, which may be locatedanywhere in the system. The passageway can also be made by mechanicalrupture of the layers while the system is in use. The passageway has aminimum diameter which is dependent on the size of the drug crystals.The diameter of the passageway must be greater than the average lengthof the drug crystals. The maximum diameter is also approximately fixed.It may only be so large that the entry of the aqueous body fluid intothe therapeutic system by convection is avoided. An exact description ofthe passageway and of the maximum and minimum dimensions will be foundin U.S. Pat. Nos. 3,485,770 and 3,916,899 and in the drawings pertainingthereto.

The therapeutic system may differ in shape and be e.g. round, oval,tubular and the like, and may also differ in size, depending on themount of fill material. Furthermore, the therapeutic system can betransparent, colourless or coloured, so as to impart an individualappearance or immediate identification to the product.

The oral therapeutic system of this invention has valuablepharmacological properties and can be used in particular for thetreatment of severe painful conditions and convulsions of differentprovenance, e.g. for the treatment of epilepsy. The use of the abovedescribed therapeutic system for the treatment of these diseases,especially epilepsy, constitutes a further object of the invention.

The present invention relates preferably to an oral therapeutic systemcomprising

(a) a wall made of acylated cellulose, e.g. cellulose acetate, which ispermeable to water but impermeable to the components of thedrug-containing core and to the ions present in body fluids, e.g.gastric or intestinal juices,

(b) a core containing freely particulate carbamazepine as drug,hydroxymethyl cellulose as protective colloid, a 1:1 mixture (% byweight) of a copolymer of vinylpyrrolidone and vinyl acetate and ahomopolymer of ethylene oxide as swellable hydrophilic polymer, sodiumor potassium chloride, glucose or mannitol as agent for inducingosmosis, as well as further pharmaceutically acceptable excipients, and

(c) a passageway through the wall (a) for delivering the componentspresent in the core to the environmental aqueous body fluid.

Most preferably the invention relates to an oral therapeutic systemcomprising

(a) a wall made of acylated cellulose, e.g. cellulose acetate, which ispermeable to water but impermeable to the components of thedrug-containing core and to the ions present in body fluids, e.g.gastric or intestinal juices,

(b) a core containing carbamazepine as drug, hydroxypropylmethylcellulose as protective colloid, a 1:1 mixture (% by weight) of acopolymer of vinylpyrrolidone and vinyl acetate having a molecularweight of 60,000±15,000 and having a monomer ratio of c. 60:40 (% byweight) and a homopolymer of ethylene oxide having a degree ofpolymerisation of 2000 to 100,000 as swellable hydrophilic polymer,sodium or potassium chloride, glucose or mannitol as agent for inducingosmosis, and (c) a passageway through the wall (a) for delivering thecomponents present in the core to the environmental aqueous body fluid.

First and foremost, the invention relates to a therapeutic system forthe peroral administration of carbamazepine having the formulation asindicated in the Examples.

The therapeutic system of this invention is prepared by methods whichare known per se, e.g. by mixing the components of the core together andcompressing them, coating the core with a semi-permeable wall and, ifappropriate, providing a passageway through said semi-permeable wall,e.g. an orifice. In a preferred embodiment of the process of thisinvention, an anhydrous crystal form of carbamazepine is comminuted toan average particle size of 5 μm. These particles, preferablymicrocrystals, are mixed with the components forming the core of thedosage form and the mixture is granulated, e.g. by mixing thehydroxypropyl methylcellulose or methyl cellulose used as protectivecolloid, sodium chloride and sodium lauryl sulfate (surfactant) as wellas Polyox® with the drug, adding to this mixture a solution ofpolyvinylpyrrolidone and vinyl acetate in an organic solvent, strippingoff the solvent, and granulating and drying the residue. The granulateis then compressed and punched to mouldings, e.g. tablet cores, with orwithout the addition of a lubricant such as magnesium stearate, whichcores are of conventional form and size of e.g. c. 5-12 mm in diameter(round forms) and c. 4-8 mm (in width) and c. 10-22 mm (oblong forms).

To prepare the granulate it is possible to use all solvents in which theswellable hydrophilic polymer and the other auxiliaries are soluble,preferably water or a lower alkanol such as methanol, ethanol orisopropanol.

The core containing the drug formulation can be coated with thesemi-permeable wall by coating, moulding, spraying, or immersing thecapsule in a solution of the material forming the semi-permeable wall.Another method which may be suitably used for applying thesemi-permeable membrane is the air suspension procedure. This methodcomprises suspending and tumbling the capsule cores in a stream of airand in a composition that forms the wall until the cores sat surroundedand coated by the wall. The air suspension procedure is described inU.S. Pat. No. 2,799,241 and in J. Am. Pharm. Assoc., Vol. 48, pp.451-459, and in Vol. 49, pp. 82-84, 1980. Other preferred standardprocedures are e.g. the pan coating method described in Remington'sPharmaceutical Sciences, 14th edition, pp. 1686-87.

The passageway in the send-permeable wall can subsequently be producedby mechanical or laser drilling. The following Examples illustrate theinvention in more detail without limiting the scope thereof.

EXAMPLE 1 Therapeutic system for TEGRETOL® 200 mg) Core

    ______________________________________                                        anhydrous carbamazepine (Tegretol ®)                                                                 200     mg                                         microcrystalline cellulose (Avicel ®),                                                               20      mg                                         FMC Corporation, Philadelphia)                                                hydroxypropyl methylcellulose (Pharmacoat ® 603,                                                     12.5    mg                                         Shin-Etsu Chem. Co., Tokyo)                                                   copolymer of vinylpyrrolidone and vinyl                                                                  80      mg                                         acetate 60:40 (Kollidon ® VA 64, BASF                                     Ludwigshafen)                                                                 polyethylene glycol (mol. wt. 5 × 10.sup.6,                                                        80      mg                                         Polyox ®, coagulant, Union Carbide)                                       sodium chloride (puriss.)  80      mg                                         sodium lauryl sulfate (puriss.)                                                                          6       mg                                         magnesium stearate (puriss.)                                                                             11.5    mg                                                                    = 490   mg                                         Semi-permeable wall                                                           cellulose acetate (32.0) (puriss.)                                                                       16      mg                                         cellulose acetate (39.9) (puriss.)                                                                       20      mg                                         polyethylene glycol 4000   4       mg                                                                    = 40    mg                                         Total weight               530     mg                                         ______________________________________                                    

Anhydrous carbamazepine, hydroxypropyl methylcellulose, sodium chlorideand sodium lauryl sulfate are mixed in a planetary mixer. This mixtureis granulated with one part of the copolymer of vinylpyrrolidone andvinyl acetate, dissolved in a mixture of methanol and isopropanol. Themixture is passed through a sieve and the resultant granulate is vacuumdried.

The dry granulate is mixed with the remainder of the copolymer ofvinylpyrrolidone and vinyl acetate, Avicel® and magnesium stearate. Thehomogeneous mixture is subsequently compressed and punched to tabletcores (punch dimensions: 10 mm, R15).

The cores are coated in a fluidised bed coater (Aeromatic Strea® 1) withan organic lacquer containing the components of the semi-permeable wall.The coated tablets are dried in an oven at 40° C. for 48 hours. Anorifice of 750 μm diameter is drilled with a mechanical drill or with alaser.

EXAMPLE 2 Therapeutic system for TEGRETOL® (200 mg) Core

    ______________________________________                                        anhydrous carbamazepine (Tegretol ®)                                                                 200     mg                                         microcrystalline cellulose (Avicel ®,                                                                20      mg                                         FMC Corporation, Philadelphia)                                                hydroxypropyl methylcellulose (Pharmacoat ® 603,                                                     13      mg                                         Shin-Etsu Chem. Co., Tokyo)                                                   copolymer of vinylpyrrolidone and vinyl                                                                  80      mg                                         acetate 60:40 (Kollidon ® VA 64, BASF                                     Ludwigshafen)                                                                 hydroxyethyl cellulose (Tylose ® H 4000 PHA)                                                         80      mg                                         glucose (puriss.)          90      mg                                         sodium lauryl sulfate (puriss.)                                                                          7       mg                                         magnesium stearate (puriss.)                                                                             10      mg                                                                    = 500   mg                                         ______________________________________                                    

Semi-Permeable Wall

    ______________________________________                                        cellulose acetate (32.0) (puriss.)                                                                    16     mg                                             cellulose acetate (39.9) (puriss.)                                                                    20     mg                                             polyethylene glycol 4000                                                                              4      mg                                                                     = 40   mg                                             Total weight            540    mg                                             ______________________________________                                    

Preparation is as described in Example 1. Hydroxyethyl cellulose is usedas swellable hydrophilic polymer instead of polythylene glycol (mol. wt.5×10⁶). Glucose is used instead of sodium chloride as agent for inducingosmosis. The granulate is prepared by mixing the components with anethanolic solution which contains one part of Kollidon® VA 64.

EXAMPLE 3 Therapeutic system for TEGRETOL® 200 mg) Core

    ______________________________________                                        anhydrous carbamazepine (Tegretol ®)                                                                 200     mg                                         microcrystalline cellulose (Avicel ®,                                                                20      mg                                         FMC Corporation, Philadelphia)                                                hydroxypropyl methylcellulose (Pharmacoat ® 603,                                                     12.5    mg                                         Shin-Etsu Chem. Co., Tokyo)                                                   copolymer of vinylpyrrolidone and vinyl                                                                  81.3    mg                                         acetate 60:40 (Kollidon ® VA 64, BASF                                     Ludwigshafen                                                                  polyethylene glycol (mol. wt. 5 × 10.sup.6,                                                        80      mg                                         Polyox ®, coagulant, Union Carbide)                                       sodium lauryl sulfate (puriss.)                                                                          6       mg                                         magnesium stearate (puriss.)                                                                             10.2    mg                                                                    = 410   mg                                         ______________________________________                                    

Semi-Permeable Wall

    ______________________________________                                        cellulose acetate (32.0) (puriss.)                                                                    16     mg                                             cellulose acetate (39.9) (puriss.)                                                                    20     mg                                             polyethylene glycol 4000                                                                              4      mg                                                                     = 40   mg                                             Total weight            450    mg                                             ______________________________________                                    

Preparation of the oral therapeutic system is as described in Example 1.The use of an osmotic agent is dispensed with.

EXAMPLE 4 Therapeutic system for TEGRETOL® 200 mg) Core

    ______________________________________                                        anhydrous carbamazepine (Tegretol ®)                                                                 200     mg                                         hydroxypropyl methylcellulose (Pharmacoat ® 603,                                                     25      mg                                         Shin-Etsu Chem. Co., Tokyo)                                                   hydroxyethyl cellulose (Natrosol ® 250L,                                                             25      mg                                         Hercules)                                                                     hydroxyethyl cellulose (Natrosol ® 250H)                                                             25      mg                                         mannitol (puriss.),        215     mg                                         sodium lauryl sulfate (puriss.)                                                                          5       mg                                         magnesium stearate (puriss.)                                                                             5       mg                                         ______________________________________                                    

    ______________________________________                                        cellulose acetate (32.0) (puriss.)                                                                      18.9   mg                                           cellulose acetate (39.8) (puriss.)                                                                      2.8    mg                                           hydroxypropyl methylcellulose 15 CPS                                                                    2.1    mg                                           polyethylene glycol 8000  2.1    mg                                                                     = 26   mg                                           Total weight              526    mg                                           ______________________________________                                    

Preparation is as described in Example 1. Hydroxyethyl cellulose is usedas swellable hydrophilic polymer instead of polyethylene glycol andKollidon ®. Mannitol is used instead of sodium chloride as agent forinducing osmosis. The granulate is prepared by mixing the componentswith an ethanolic solution which contains 1 part of the hydroxyethylcellulose employed.

What is claimed is:
 1. An oral therapeutic system for administeringcarbamazepine comprising(a) a wall made of acylated cellulose which ispermeable to water but impermeable to the components of the drugcontaining core and to the ions present in gastric or intestinal juices;(b) a core containing finely particulate carbamazepine as a drug,hydroxypropylmethyl cellulose as protective colloid, a swellablehydrophilic polymer selected from the group consisting ofpoly-N-vinyl-2-pyrrolidone, polyvinyl alcohol, alkylene oxidehomopolymers, methyl cellulose, ethyl cellulose, hydroxypropylcellulose, the copolymer of vinylpyrrolidone and vinyl acetate, themixture of the copolymer of vinylpyrrolidone and vinyl acetate and thehomopolymer of ethylene oxide and, a water soluble compound for inducingosmosis; and (c) a passageway through the wall (a) for delivering thecomponents present in the core to the environmental gastric orintestinal juices.
 2. An oral therapeutic system according to claim 1,comprising(a) a wall made of acylated cellulose which is permeable towater but impermeable to the components of the drug-containing core andto the ions present gastric or intestinal juices, (b) a core containingfinely particulate carbamazepine as drug, hydroxymethyl cellulose asprotective colloid, a 1:1 mixture % by weight of a copolymer ofvinylpyrrolidone and vinyl acetate and a homopolymer of ethylene oxideas swellable hydrophilic polymer, and and (c) passageway through thewall (a) for delivering the components present in the core to theenvironmental aqueous body fluid.
 3. An oral therapeutic systemaccording to claim 1, comprising(a) a wall made of cellulose acetatewhich is permeable to water but impermeable to the components of thedrug-containing core and to the ions present in gastric or intestinaljuices, (b) a core containing carbamazepine as drug, hydroxypropylmethylcellulose as protective colloid, a 1:1 mixture % by weight of acopolymer of vinylpyrrolidone and vinyl acetate having a molecularweight of 60.000±15,000 and having a monomer ratio of 60:40% by weightand a homopolymer of ethylene oxide having a degree of polymerisation of2000 to 100,000 as swellable hydrophilic polymer, and (c) a passagewaythrough the wall (a) for delivering the components present in the coreto the environmental gastric or intestinal juices.
 4. An oraltherapeutic system according to claim 1, which contains anhydrousmicrocrystals of carbamazepine.
 5. An oral therapeutic system accordingto claim 1, which contains anhydrous microcrystals of carbamazepinehaving a size of up to 20 μm, and hydroxypropyl methylcellulose asprotective colloid.
 6. The therapeutic system of claim 2 furthercomprising a compound for inducing osmosis selected from sodiumchloride, potassium chloride, glucose, and mannitol.
 7. The therapeuticsystem of claim 3 further comprising a compound for inducing osmosisselected from sodium chloride, potassium chloride, glucose and mannitol..Iadd.
 8. An oral therapeutic system for administrating carbamazepinecomprising(a) a wall made of acylated cellulose which is permeable towater but impermeable to the components of the drug containing core andto the ions present in gastric or intestinal juices; (b) a corecontaining finely particulate carbamazepine as a drug,hydroxypropylmethyl cellulose as protective colloid, a swellablehydrophilic polymer selected from the group consisting ofpoly-N-vinyl-2-pyrrolidone, polyvinyl alcohol, alkylene oxidehomopolymers, methyl cellulose, ethyl cellulose, hydroxypropylcellulose, hydroxyethyl cellulose, the copolymer of vinyl pyrrolidoneand vinyl acetate, the mixture of the copolymer of vinylpyrrolidone andvinyl acetate and the homopolymer of ethylene oxide and, a water solublecompound for inducing osmosis; and (c) a passageway through the wall (a)for delivering the components present in the core to the environmentalgastric or intestinal juices. .Iaddend. .Iadd.9. The oral therapeuticsystem of claim 8 wherein 2 swellable hydrophilic polymers are present..Iaddend. .Iadd.10. The oral therapeutic system of claim 8 wherein saidcarbamazepine is present as anhydrous microcrystals. .Iaddend. .Iadd.11.The oral therapeutic system of claim 10 wherein carbamazepinemicrocrystals have a size of up to 20um, and said protective colloid ishydroxypropyl methylcellulose. .Iaddend. .Iadd.12. The oral therapeuticsystem of claim 8 further comprising a compound for inducing osmosisselected from sodium chloride, potassium chloride, and carbohydrates..Iaddend. .Iadd.13. The oral therapeutic system of claim 11 furthercomprising a compound for inducing osmosis selected from sodiumchloride, potassium chloride, and carbohydrates. .Iaddend. .Iadd.14. Theoral therapeutic system of claim 8 wherein said core comprises anhydrouscarbamazepine, hydroxypropyl methylcellulose, hydroxyethylcellulose, andmannitol. .Iaddend. .Iadd.15. The oral therapeutic system of claim 8wherein said wall comprises cellulose acetate, hydroxypropylmethylcellulose, and polyethylene glycol
 8000. .Iaddend.